Azithromycin: the first of the tissue-selective azalides

Hoepelman, I. M.; Schneider, Margriet M E

doi:10.1016/0924-8579(95)00009-w

Cited by 64 publications

(41 citation statements)

References 129 publications

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“…Only on day 10, i.e., 5 days after the last azithromycin dose, did drug concentrations seem to equilibrate between plasma and soft tissues. These findings are in marked contrast to the vast majority of data on tissue PK of azithromycin available in the literature so far, where azithromycin tissue concentrations are reported to remain on a high level even after the end of treatment and in any case to exceed drug concentrations in plasma (11,12,23,38).…”

Section: Discussioncontrasting

confidence: 95%

“…According to this hypothesis, it was speculated that WBC might transport the drug, which retains its antimicrobial properties in spite of being trapped inside lysosomal compartments (10,35,36), to the site of infection and eventually release it in response to phagocytosis. Thus, WBC together with fibroblasts, which also constitute an important drug reservoir, contribute significantly to azithromycin's efficacy against intracellular pathogens (37,38).…”

Section: Discussionmentioning

confidence: 99%

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Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Matzneller

Krasniqi

Kinzig

et al. 2013

Antimicrob Agents Chemother

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cAlthough azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC 0 -24 )/MIC 90 ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

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Section: Discussioncontrasting

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Matzneller

Krasniqi

Kinzig

et al. 2013

Antimicrob Agents Chemother

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“…This is due to the fact that chemotactic drug delivery is an important determinant for drug exposure in infected tissues, as phagocytes migrate to the infection site and increase local drug concentrations by releasing AZM from their lysosomes (43). In spite of being trapped inside the lysosomal compartments of white blood cells (WBCs) or fibroblasts (44)(45)(46)(47), AZM retains its antimicrobial properties and, once released, is available for antimicrobial activity at the infection site (48,49). It has also been shown that the local pH values in the ISF can be reduced, due to the metabolic activities of infiltrating neutrophils (anaerobic glycolysis) and infecting pathogens (e.g., production of short-chain fatty acids [50,51]), which result in a further increase in local ISF concentrations.…”

Section: Discussionmentioning

confidence: 99%

Development of a Population Pharmacokinetic Model Characterizing the Tissue Distribution of Azithromycin in Healthy Subjects

Zheng

Matzneller

Zeitlinger

et al. 2014

Antimicrob Agents Chemother

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Recent clinical trials indicate that the use of azithromycin is associated with the emergence of macrolide resistance. The objective of our study was to simultaneously characterize free target site concentrations and correlate them with the MIC 90 s of clinically relevant pathogens. Azithromycin (500 mg once daily [QD]) was administered orally to 6 healthy male volunteers for 3 days. The free concentrations in the interstitial space fluid (ISF) of muscle and subcutaneous fat tissue as well as the total concentrations in plasma and polymorphonuclear leukocytes (PMLs) were determined on days 1, 3, 5, and 10. All concentrations were modeled simultaneously in NONMEM 7.2 using a tissue distribution model that accounts for nonlinear protein binding and ionization state at physiological pH. The model performance and parameter estimates were evaluated via goodness-of-fit plots and nonparametric bootstrap analysis. The model we developed described the concentrations at all sampling sites reasonably well and showed that the overall pharmacokinetics of azithromycin is driven by the release of the drug from acidic cell/tissue compartments. The model-predicted unionized azithromycin (AZM) concentrations in the cytosol of PMLs (6.0 ؎ 1.2 ng/ml) were comparable to the measured ISF concentrations in the muscle (8.7 ؎ 2.9 ng/ml) and subcutis (4.1 ؎ 2.4 ng/ml) on day 10, whereas the total PML concentrations were >1,000-fold higher (14,217 ؎ 2,810 ng/ml). The total plasma and free ISF concentrations were insufficient to exceed the MIC 90 s of the skin pathogens at all times. Our results indicate that the slow release of azithromycin from low pH tissue/cell compartments is responsible for the long terminal half-life of the drug and thus the extended period of time during which free concentrations reside at subinhibitory concentrations.

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“…Generations of macrolide antibiotics such as clarithromycin, roxithromycin and azithromycin are currently used due to their acid stability and wide distribution in tissues. [1][2][3][4][5] Interest in the electrochemical behaviour of active drug constituents has also been steadily increasing. [6][7][8] Investigation of electrode processes involving oxidation or reduction reactions may shed more light on in-vivo redox processes.…”

Section: Introductionmentioning

confidence: 99%

Mathematical Modelling of the Electrode Process of Azithromycin Using Cyclic Voltammetry at Hanging Mercury Drop Electrode

Shawabkeh

Tutunji

2002

Sensors

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Abstract:A theoretical treatment is presented to predict the kinetic behaviour of azithromycin at the surface of hanging mercury drop electrode using cyclic voltammetry. A model is developed to incorporate the occurrence of adsorption of the oxidized and reduced species of azithromycin at the surface of mercury drop electrode. An analytical solution was obtained using MATHEMATICA Wolfram Research, Inc.) to predict the cyclic voltammetric profiles by calculating the currents resulting after applying variable potentials ranging -1.9 to -1.3 V versus Ag/AgCl. Simulation runs at different initial concentrations of azithromycin and different scan rates showed good agreement with experimental findings. However, this model should be modified to describe a multilayer adsorption with irreversible electrochemical reaction.

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Azithromycin: the first of the tissue-selective azalides

Cited by 64 publications

References 129 publications

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Development of a Population Pharmacokinetic Model Characterizing the Tissue Distribution of Azithromycin in Healthy Subjects

Mathematical Modelling of the Electrode Process of Azithromycin Using Cyclic Voltammetry at Hanging Mercury Drop Electrode

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